Necroptosis is a form of programmed cell death that is executed by activation of the Receptor Interacting Protein Kinases (RIPKs), RIPK1 and RIPK3. While this cell death pathway has been the subject of intense study, physiological settings in which it is important have remained elusive. We have found that mice lacking RIPK3 are highly susceptible to infection by the neuroinvasive flavivirus West Nile virus (WNV). RIPK3 knockout animals are unable to control viral growth within the central nervous system (CNS), because they display a profound defect in the recruitment of immune cells into this tissue. Notably, RIPK3-deficient mice also fail to control Zika virus (ZIKV) infection, and display neurological impairments and ascending paralysis upon infection with this pathogen. Surprisingly, the protective role of RIPK3 in this setting is wholly independent of its role in inducing programmed cell death; rather, RIPK3 is required for normal production of inflammatory chemokines and immune cell trafficking in the WNV-infected CNS. Given these unexpected preliminary data, the central hypothesis of this application is that virus-induced RIPK3 activation within the CNS does not trigger cell death, but rather activates an inflammatory transcription program is required for neuroinflammation, immune cell recruitment, and host protection. This application will investigate this hypothesis by focusing on three Aims. First, we will work to understand how RIPK3 is engaged within the CNS to promote host protection, using conditional deletion and transgenic expression of RIPK3 within this tissue in combination with cutting-edge imaging approaches. Next, we will use biochemical methods and novel mouse models to understand the downstream targets of RIPK3 that are responsible for the coordination of neuroinflammation. Finally, we will investigate the role of RIPK3 in host protection against ZIKV infection, and investigate the unexpected defects in motor function observed in ZIKV-infected RIPK3 knockout mice. Together, this work will define a novel signaling pathway responsible for host defense against neuroinvasive viral pathogens that represent a significant threat to global health.